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WO2005070080A2 - Procedes d'utilisation de zonisamide comme therapie auxiliaire pour des crises partielles - Google Patents

Procedes d'utilisation de zonisamide comme therapie auxiliaire pour des crises partielles Download PDF

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Publication number
WO2005070080A2
WO2005070080A2 PCT/US2005/000469 US2005000469W WO2005070080A2 WO 2005070080 A2 WO2005070080 A2 WO 2005070080A2 US 2005000469 W US2005000469 W US 2005000469W WO 2005070080 A2 WO2005070080 A2 WO 2005070080A2
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WIPO (PCT)
Prior art keywords
zonisamide
patient
pancreatitis
therapy
symptoms
Prior art date
Application number
PCT/US2005/000469
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English (en)
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WO2005070080A3 (fr
Inventor
Ivan Lieberbirg
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Eisai Inc.
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Publication date
Application filed by Eisai Inc. filed Critical Eisai Inc.
Publication of WO2005070080A2 publication Critical patent/WO2005070080A2/fr
Publication of WO2005070080A3 publication Critical patent/WO2005070080A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to methods of improving the safety of patients who are receiving administrations of zonisamide (3-benzisoxazole methylene sulfonamide) and those who are in need of zonisamide therapy.
  • Background of the Invention [002] In the United States, over 2 million serious adverse drug reactions (ADRs) occur ever year, with 100,000 associated deaths. This places ADRs as the fourth leading cause of death, ranking ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.
  • zonisamide therapy in a very small percentage of patients (available estimates in the United States are about one in seven thousand four hundred fifty-five (1:7,455)) can precipitate acute pancreatitis. It also has been found that by curtailing (either by removal, reduction, or tapering off) the administration of zonisamide dosing, alone or in conjunction with other concomitant medications, alleviation and minimization of this severe adverse event is possible. This is particularly the case when medical intervention to manage the disease and/or removal, reduction, or tapering off of zonisamide is instituted rapidly.
  • the present invention is directed to methods of using zonisamide for a regulatory agency approved use (e.g., as an adjunctive therapy for partial seizures).
  • the methods improve the safety of zonisamide therapy for patients receiving administrations of the drug, or those who are in need fzonisamide therapy.
  • the methods of using zonisamide as an adjunctive therapy for partial seizures improves the safety and health of patients taking zonisamide by increasing the awareness of the patient or patient's guardian that pancreatitis is a possible side effect.
  • a patient may be provided with a therapeutically effective amount of zonisamide, and the patient or the patient's guardian may be informed that abdominal pain, hypovolemia, shock, nausea, anorexia, vomiting, or abdominal distention are symptoms of pancreatitis that require prompt medical evaluation if such symptoms are experienced by the patient.
  • the patient or patient's guardian can self-monitor for signs and symptoms of pancreatitis, and seek medical attention if such symptoms occur in order to obtain appropriate tests, diagnosis, and treatment.
  • the present methods reduce the risk of pancreatitis in patients receiving zonisamide therapy.
  • the present invention provides methods of using zonisamide as an adjunctive therapy for partial seizures comprising informing a prescribing physician or other medical professional (e.g., an emergency medical worker) that pancreatitis may result from zonisamide therapy and to monitor a patient who is prescribed zonisamide as an adjunctive therapy for partial seizures for abdominal pain, hypovolemia, shock, nausea, anorexia, vomiting, or abdominal distention.
  • a prescribing physician or other medical professional also may be advised that when abdominal pain, hypovolemia, shock, nausea, anorexia, vomiting, or abdominal distention is observed, an appropriate diagnostic be employed to determine whether pancreatitis is present.
  • the prescribing physician or other medical professional may be advised to remove, reduce, or taper off the zonisamide dosing in the patient, and initiate appropriate supportive therapy for the underlying condition(s).
  • the present methods enable prescribing physicians and other health care professionals to recognize and minimize the risk associated with and adverse event, namely pancreatitis, which may occur in some patients who receive zonisamide therapy.
  • the present methods also include methods of administrating zonisamide as an adjunctive therapy for partial seizures comprising providing packaging that includes a pharmaceutical formulation of zonisamide along with information providing a warning that zonisamide may cause pancreatitis in some patients and that one or more symptoms chosen from the group of abdominal pain, hypovolemia, shock, nausea, anorexia, vomiting, and abdominal distention are potentially signs of pancreatitis; and providing the packaging to a patient who has been prescribed zonisamide.
  • the medical information provided in any of the above described methods concerning the signs and symptoms of pancreatitis may alternatively be provided in layman's terms, so as to be better understood by patients or non-medical professionals.
  • Zonisamide is an antiseizure drug, chemically classified as a sulfonamide and unrelated to other antiseizure agents. Antiepileptic drugs are commonly abbreviated as "AEDs.”
  • AEDs Antiepileptic drugs
  • Zonisamide was approved in 2000 for the adjunctive treatment, i.e., taken in conjunction with one or more other AED, treatment of epilepsy in the United States. It was first introduced in Japan approximately 12 years ago, where it also has been used as monotherapy, i.e., without other AEDs as concomitant therapeutics.
  • Zonisamide is not known to be' a hepatic enzyme inducer and has been administered adjunctively with almost all of the other regulatory- approved AEDs either in the United States or abroad.
  • zonisamide may produce antiseizure effects through action at sodium and calcium channels.
  • zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca 2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization, thus suppressing hyperexcitablity in epileptic foci.
  • T-type Ca 2+ currents voltage-dependent, transient inward currents
  • zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion, which does not produce changes in chloride flux.
  • zonisamide (10-30 pg/mL) suppresses synaptically-driven electrical activity without affecting postsyriapticGABA or, glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [ 3 H]-GABA (rat hippocampal slices ⁇ .
  • glutamate responses cultured mouse spinal cord neurons
  • neuronal or glial uptake of [ 3 H]-GABA rat hippocampal slices ⁇ .
  • zonisamide does not appear to potentiate the synaptic activity of GAGA.
  • In vivo microdialysis studies demonstrated that zonisamide facilities both dopaminergic and serotonergic neurotransmission.
  • Zonisamide also has weak carbonic anhydrase inhibiting activity (about l/50 th the inhibition compared to acetazolamide), and this pharmacologice effect is not thought to be a major contributing factor in the anti-seizure activity of zonisamide.
  • ZONEGRAN ® the human therapeutic pharmaceutical formulation containing zonisamide
  • ZONEGRAN ® is indicated as adjunctive therapy for the treatment of partial seizures in adults and is supplied by prescription in the form of 25, 50, and 100 mg capsules. The capsule may be divided, so as to offer smaller increments in dosage. Recommended dosing is once or twice daily, the recommended daily dose of 100 mg at the initiation of therapy should not be divided.
  • ZONEGRAN ® is given orally and can be taken with or without food.
  • the initial dose should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level.
  • valproate DEPAKOTE®, valproate (sodium salt): valproic acid 1:1
  • zonisamide has not been known to cause pancreatitis in patients receiving ZONEGRAN® therapy.
  • zonisamide may independently induce acute pancreatitis (AP) in a small number of patients, and has implicated AP in patients receiving zonisamide as an adjunctive therapy. Accordingly, the present invention is directed to methods of increasing the safety of zonisamide therapy in view of its newly discovered role in pancreatitis.
  • Acute pancreatitis is defined as an acute inflammatory process of the pancreas with variable involvement of peripancreatic tissues or remote organ systems.
  • AP acute pancreatitis
  • a review article containing the current classification, definition and terminology, epidemiology and etiology, pathogenesis and pathological findings, clinical and laboratory findings, and as well as more modern techniques of pancreatic imaging and the associated findings, with emphasis on cross-sectional imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging can be found in Merkle, Elmar M. et al., European Radiology (Germany) 12(8) p. 1979-92 (August 2002), which is hereby incorporated by reference in its entirety. [023] .
  • Acute pancreatitis causes pathologic changes in the pancreas ranging from a mild edematous process to an overwhelming necrotizing lesion, which may be fatal. While its symptoms are variable, it is principally characterized by epigastric pain radiating to either the upper quadrant or directly through to the back, and of frequently shock develops due to circulating vasoactive substances or retroperitoneal hemorrhage. The typical pain is gnawing, of sudden onset, of exceeding severity, unremitting, and sometimes colicky in character. It is not relived by vomiting, which is another symptom of pancreatitis, and is little affected by morphine, for example. Other symptoms common in pancreatitis are nausea, anorexia and shock (also referred to as hypovolemia).
  • pancreatitis After 48 to 72 hours, even with continuing evidence of pancreatitis, total serum amylase levels tend to return to normal; therefore, serum lipase levels are measured for elevated levels concomitantly in making a diagnosis. Serum lipase activity increases in parallel with amylase activity, and measurement of both increases the diagnostic yield. [025] Other means of diagnosing pancreatitis are available and known to those of skill in the art.
  • CT scans computerized tomography
  • Ca m Cc r urine amylase:creatine clearance ratio
  • CECT contrast-enhanced dynamic CT scan
  • Ascitic fluid is a serous effusate that accumulates in the abdominal cavity, in the present application, as a result of AP. It was suggested that peritoneal lavage removed some toxic substance(s) within the PAAF.
  • ARDS adult respiratory distress syndrome
  • Hepatic mitochondria respiration and oxygen consumption was diminished in vitro when hepatic cells were exposed to PAAF.
  • This toxin therefore, was not specific for one cell or tissue type; in fact, it had profound effects on all organ systems examined.
  • a standard traditional rationale in treating AP is to "set the gland to rest.” This method of treatment is implemented by restricting the intake of food, administering fluids, and maintaining electrolyte balance in afflicted patients.
  • the severity of the disease is usually rated as mild (abdominal pain and tension), moderate (tension with guarding and paralytic ileus), or severe (paralytic ileus with diffused peritonitis and/or shock).
  • the level of severity determines the type of medical treatment necessary to support the patient. The more severe the disease the closer the monitoring and medical intervention is required.
  • zonisamide should ordinarily be removed, reduced, or alternatively tapered down to an acceptable level, and alternative treatment for the underlying medical condition may be initiated as clinically indicated. If another cause for the attack is identified, e.g., ethanol, pancreatic duct obstruction, etc., then it would be possible to carefully rechallenge with zonisamide once the acute attack of AP has subsided. If the patient again appears to be developing AP or is diagnosed with AP, then switching to another AED may be warranted.
  • another cause for the attack e.g., ethanol, pancreatic duct obstruction, etc.
  • a hospital physician or emergency medical personnel will have access to other pharmacological interventions for short-term control of generalized seizure activity such as either intravenous lorazepam, at a dose of 0.1 mg/kg, or diazepam at 0.2 mg/kg. If sedatives prove insufficient, then a patient also may be administered fosphenytoin, or in status epilepticus, phenobarbital, with careful monitoring for respiratory depression. Intravenous administration is preferred since this route will provide the most rapid attainment of therapeutic serum levels. Additionally, at the treating physician's discretion, an alternate AED may be substituted for zonisamide.
  • pancreatitis For adverse events reported as pancreatitis:
  • pancreatitis cases originated in the United States. Of the ten (10) cases, three (3) were pediatric cases, six (6) were adult cases, and one (1) was of unknown age. Of the ten (10) cases, four (4) recovered, two (2) were recovering at time of report, three (3) had not recovered, and one (1) had an unknown outcome. None of these events were fatal! The development of pancreatitis occurred between three (3) days and three (3) to four (4) months of the initiation of zonisamide treatment.
  • pancreatitis cases Of the ten (10) pancreatitis cases, five (5) cases had strong confounding factors, and seemed to be unrelated to zonisamide, but the possibility of zonisamide involvement could not be .completely excluded. Four (4) cases had weak confounding factors, and zonisamide involvement may be possible. One (1) case did not seem to have relevant confounding factors, and zonisamide involvement seems possible. One (1) case did not seem to have relevant confounding factors, and zonisamide involvement seems possible.
  • pancreatitis occurred during zonisamide treatment with no or only weak confounding factors present. All these cases occurred in the US and there were no cases of pancreatitis from Japanese sources with no or only weak confounding factors reported. This amounts to an estimated incidence of 1:7,455 based upon estimated US exposure. This represents a combined estimated incidence of 1:244,491 based upon the combined estimates of Japanese and US exposure.
  • the estimated number of patients exposed to zonisamide in the U.S. and Japan is 1,222,453 unique patients. This is a rather conservative estimate, assuring that the number of patients actually exposed to zonisamide is unlikely to be higher than the estimate provided. Similarly, the incidences of pancreatitis estimated herein are unlikely to be higher than calculated.
  • pancreatitis and amylase/lipase increase in the US exposed population is 1:6,213, based on combining the reported cases of pancreatitis and amylase/lipase increase. There were no cases of pancreatitis and amylase/lipase increase from Japanese sources. This represents a combined estimated incidence of 1:203,742 based upon the combined estimates of Japanese and US exposure.
  • Example 1 A 40-year old patient experienced acute pancreatitis and an elevated DBLANTIN ® (phenytoin) plasma level during the use of ZONEGRAN ® .
  • the patient has been administered ZONEGRAN ® 400mg daily and DILANTIN ® 600mg daily for the past 3 to 4 months.
  • the patient was hospitalized with symptoms of DILANTIN ® toxicity (plasma level of 24 to 25 mcg/ml), amylase and lipase levels in the 2000' s U L, abdominal discomfort, and nausea.
  • the patient was diagnosed with acute pancreatitis (AP); however, a gastroenterology work-up could not identify a cause for AP.
  • AP acute pancreatitis
  • the DILANTIN ® dose was reduced and the patient was tapered off ZONEGRAN ® . Subsequently, the patient's amylase and lipase levels decreased. The fact that the patient's AP subsided while still on phenytoin (at reduced doses) but only after zonisamide was tapered off, would indicate that zonisamide was the offending agent in this instance.
  • Example 2 An 83-year old female patient receiving zonisamide for treatment of neuropathic pain developed difficulty breathing, fever, disorientation/confusion, kidneys "not working well," irregular heart rate, elevated heart rate, elevated glucose level, and pancreatitis during the use of ZONEGRAN ® for neuropathy of her feet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

La présente invention a trait à des procédés d'utilisation de zonisamide comme thérapie auxiliaire pour des crises partielles. En particulier, les procédés améliorent la sécurité des patients prenant des préparations pharmaceutiques de zonisamide en fournissant une information qui les avertit contre l'apparition de la pancréatite comme étant un effet secondaire possible ; dans lesquels les patients et/ou les médecins prescripteurs et d'autres prestataires de soins médicaux sont avertis pour la surveillance concernant la pancréatite et utilisent des procédés qui vont améliorer le résultat thérapeutique chez les quelques patients qui souffrent de pancréatite associée au traitement de zonisamide.
PCT/US2005/000469 2004-01-08 2005-01-10 Procedes d'utilisation de zonisamide comme therapie auxiliaire pour des crises partielles WO2005070080A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/752,515 US20050043704A1 (en) 2003-08-21 2004-01-08 Methods of using zonisamide as an adjunctive therapy for partial seizures
US10/752,515 2004-01-08

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WO2005070080A2 true WO2005070080A2 (fr) 2005-08-04
WO2005070080A3 WO2005070080A3 (fr) 2006-11-02

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US20050043704A1 (en) 2005-02-24

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